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Abstract

Cardiac remodeling is a dynamic process that is accelerated after myocardial infarction (MI). Types I and III collagen, both fibrillar collagens, have been the focus of the remodeling and repair literature. We have recently uncovered a potentially novel role for non-fibrillar type VI collagen (Col6) in post-MI repair and global LV function. We reported that Col6 null (Col6-/-) mice are protected from ischemic injury as evidenced by significantly reduced infarct sizes and preserved systolic function. Interestingly, the Col6-/- mouse, originally developed as a model for a skeletal muscle dystrophy known as Bethlem Myopathy, allowed for the discovery that type VI collagen mutations or knockout led to mitochondrial dysfunction and skeletal myocyte apoptosis with aging. Our hypothesis that altered mitochondrial structure and function in the myocardium of Col6-/- mice is the mechanistic basis of the paradoxical protection from ischemic injury. To investigate the potential mitochondrial mechanism(s) responsible for the cardioprotection in Col6-/- mice, we began by using transmission electron microscopy (TEM) to assess mitochondrial morphology. Mitochondria from uninjured Col6-/- LV tissue had similar morphology as WT. Mitochondrial morphology at 3 days post-MI indicates that WT and Col6-/- mitochondria are compromised. However, TEMs of Col6-/- hearts 14 days post-MI show longer chains of intrerfibrillar mitochondria, whereas swollen, isolated mitochondria were apparent in WT. Interestingly, we observed a 3.0 vs. 1.7-fold increase (WT vs. and Col6-/- mice, respectively) in the fission protein Drp1 specifically in the infarcted zones at 24 hours post injury. We next measured O2 consumption 24 hours post-MI using isolated mitochondria from both phenotypes, discovering a reduced coupling of oxidative phosphorylation (44.5 ± 4.7% reduction in respiratory control index; RCI) in Col6-/- mice compared to WT controls. However, the RCI of the infarcted region in Col6-/- 24 hours post-MI hearts did not significantly decline compared to WT. Together, these data indicate that Col6-/- mice have preserved mitochondrial morphology and respiration following MI and may be a mechanism underlying the unexpected cardioprotection from MI injury in Col6-/- mice.